The fragile X syndrome (FXS), a type of inherited mental retardation (MR), is due to the silencing of the FMR1 X-linked gene. In over 95 percent of the cases, the mutation is due to an expansion of an unstable CGG repeat sequence located in the 5' untranslated region of the gene. Once expanded to over 200 repeats, the FMR1 gene is hypermethylated and consequently no message is transcribed. In the previous grant, the investigators suggested that, in addition to this specific mutation and resulting MR, there may also be a phenotype associated with an increased number of CGG repeats, i.e., alleles with 41 to 100 repeats. Although not methylated, the mRNA of such FMR1 alleles may be altered or alter the binding properties of other proteins. Preliminary results suggest that an increased number of CGG repeats may influence an individual's cognitive and behavioral performance and, for females, affect the age at menopause. If confirmed, this gene may be one of the first clearly identified genes to affect cognitive and behavioral skills and will become one of the possible candidate genes that play a role in psychiatric and behavioral disorders. As the frequency of such FMR1 alleles is high in the population, about 3 percent, the impact on the population may be greater than that related to the mutation leading to the FXS. Moreover, a proportion of these high repeat alleles may be unstably inherited, although that proportion is unknown and factors that influence that instability are not fully understood. In this revised application, the researchers propose to survey a cross-section of the general population and FXS families to obtain a large sample of probands with high repeat alleles. First they will assess all probands with neuropsychological tests to confirm or refute the phenotype consequence of these alleles. Second, they will ascertain parents of probands and conduct a case control study to further examine the relationship between repeat number and the age at menopause in carriers with the high repeat alleles. Lastly, they will ascertain first degree relatives of probands to obtain an estimate of the proportion of unstable alleles in the general population.